1. Field of the Invention
The invention concerns novel synthetic polypeptides useful in the diagnosis and treatment of multiple sclerosis; intermediates and derivatives thereof.
2. Brief Description of the Prior Art
It has been reported that the basic protein isolated from myelin of the central nervous system of man and animals induces experimental allergic encephalomyelitis (EAE), an auto-immune disease of the central nervous system. The structure for the basic protein was published by E. H. Eylar, Steven Brostoff, George Hashim, Juanita Caccam, and Paul Burnett entitled "Basic Al Protein of the Myeline Membrane", The Journal of Biological Chemistry,Vol. 246, No. 18, Issue of Sept. 25, 1971, pp. 5770-5784. Also, it has been shown that the disease inducing basic protein is readily hydrolyzed by proteolytic enzymes. It is also known that there is more than one disease inducing region found on the native basic protein molecule. These regions have been isolated in the form of peptides following hydrolysis of the basic protein. The essential requirement for disease induction in the guinea pig is the linear sequence of at least nine amino acid residues having the schematic formula: EQU H--Phe--Ser--Trp--Gly--Ala--Glu--Gly--Gln--Lys--OH
For convenience, the amino acid groups in the above formula, and at times hereinafter, are referred to by abbreviations, following accepted and common practice in peptide chemistry. For example, the following abbreviations for amino acids are used, at times, throughout the following specification and claims:
Lys--lysine PA1 His--histidine PA1 Arg--arginine PA1 Thr--threonine PA1 Ser--serine PA1 Glu--glutamic acid PA1 Pro--proline PA1 Gln--glutamine PA1 Gly--glycine PA1 Ala--alanine PA1 Leu--leucine PA1 Ileu--isoleucine PA1 Tyr--tyrosine PA1 Trp--tryptophan PA1 Phe--phenylalanine PA1 mono, di-, and trichloracetic acid; PA1 .alpha. and .beta.-chloropropionic acid PA1 .alpha. and .gamma.-bromobutyric acid; PA1 .alpha. and .delta.-iodovaleric acid; PA1 mevalonic acid; PA1 2- and 4-chlorocyclohexanecarboxylic acid; PA1 shikimic acid; PA1 2-nitro-1-methyl-cyclobutanecarboxylic acid; PA1 1,2,3,4,5,6-hexachlorocyclohexanecarboxylic acid; PA1 3-bromo-2-methylcyclohexanecarboxylic acid; PA1 4- and 5-bromo-2-methylcyclohexanecarboxylic acid; PA1 6-bromo-2-methylcyclohexanecarboxylic acid; PA1 2,3-dibromo-2-methyl-cyclohexanecarboxylic acid; PA1 2,5-dibromo-2-methylcyclohexanecarboxylic acid; PA1 4,5-dibromo-2-methylcyclohexanecarboxylic acid; PA1 5,6-dibromo-2-methylcyclohexanecarboxylic acid; PA1 3-bromo-3-methylcyclohexanecarboxylic acid; PA1 6-bromo-3-methylcyclohexanecarboxylic acid; PA1 1,6-dibromo-3-methylcyclohexanecarboxylic acid; PA1 2-bromo-4-methylcyclohexanecarboxylic acid; PA1 1,2-dibromo-4-methylcyclohexanecarboxylic acid; PA1 3-bromo-2,2,3-trimethylcyclopentanecarboxylic acid; PA1 1-bromo-3,5-dimethylcyclohexanecarboxylic acid; PA1 homogentisic acid, o-, m-, and p-chlorobenzoic acid; PA1 anisic acid; PA1 salicylic acid; PA1 p-hydroxybenzoic acid; PA1 .beta.-resorcyclic acid; PA1 gallic acid; PA1 veratric acid; PA1 2,4,6-trimethoxybenzoic acid; PA1 2,4,6-trimethoxycinnamic acid; PA1 4,4'-dichlorobenzilic acid PA1 o-, m-, and p-nitrobenzoic acid; PA1 cyanoacetic acid; PA1 3,4- and 3,5-dinitrobenzoic acid; PA1 2,4,6-trinitrobenzoic acid; PA1 thiocyanoacetic acid; PA1 1-cyanopropionic acid; PA1 lactic acid; PA1 ethoxyformic acid (ethyl hydrogen carbonate); PA1 butyloxyformic acid; PA1 pentyloxyformic acid; PA1 hexyloxyformic acid; PA1 dodecyloxyformic acid; PA1 hexadecyloxyformic acid; and the like.
In each instance herein, it should be understood that in referring to amino acids, both the D- and L-isomeric forms are intended to be identified unless otherwise indicated.
For disease induction of guinea pigs the linear sequence of amino acid residues required is of the schematic formula: EQU H--Phe--Ser--Trp--Gly--Ala--Glu--Gly--Gln--Arg--OH
and for disease induction in monkeys and rabbits the linear sequence of amino acid residues required is of the schematic formula: EQU H--Thr--Thr--His--Tyr--Gly--Ser--Leu--Pro--Gln--Lys--OH.
Investigators have shown that EAE can be induced in animals by administering a natural compound having one of the disease inducing regions of the basic proteins. Other disease inducing peptides produced from the native basic protein by hydrolysis have been isolated. The disease induced by the active regions has the same clinical and pathological manifestations as that produced when the whole protein is administered.
Unexpectedly, the administration to a mammal of the synthetic compounds of my invention does not induce disease in the mammals as occurs upon adminstration of the naturally occurring analogs.